PROJECT SUMMARY/ABSTRACT Periodontitis is initiated by a dysbiotic microbial community; however, it is the host immune response to the microbial insults that ultimately causes the damage to the tooth supporting complex. There are considerable limitations to the current standard of care for treatment of periodontal diseases, which is focused on eliminating the biofilms. Increasing evidence indicates that the susceptibility to periodontitis is largely determined by the host response. Therapies targeting the uncontrolled, overly aggressive inflammation are critical not only for blocking the diseases but also for the reconstruction of a healthy periodontal ecosystem. Epigenetic regulation such as histone acetylation is essential for inflammatory gene expression. A specific histone acetylation pattern is proposed in inflammatory diseases including periodontitis. Bromodomain and extraterminal domain (BET) proteins are the ?reader? that mediate the epigenetic marks to the transcription machinery. BET inhibitors are an emerging class of epigenetic drugs for inflammatory diseases. Recently, we found that RVX-208, a selective BET inhibitor that is being tested in a Phase 3 clinical trial for cardiovascular diseases, significantly suppresses inflammatory cytokine production and inhibits osteoclast differentiation. These findings suggested that histone acetylation and BET proteins may have important roles in periodontal inflammation, and may be potential diagnostic markers and pharmaceutical targets for periodontitis. To better understand epigenetic regulation in periodontitis and develop a novel therapeutic for periodontitis, we propose to 1) Identify the histone acetylation and BET protein expression profile in periodontitis patients; 2) Define the role of BET proteins in periodontal inflammation; 3) Determine if targeting histone acetylation by a selective BET inhibitor can ameliorate periodontal inflammation and alveolar bone loss in vivo. The proposed studies will generate critical clinical data to support the importance of epigenetic regulation in the pathogenesis of periodontal disease and help us develop the first ?epi? drug to treat the diseases. 1